Ischemic retinopathies are a disorder of pathological retinal neovascularization, which can result in life-long blindness in children and adults. These are a leading causes of blindness in the US and Western Europe. Angiogenesis regulation involves a balance between pro- and anti-apoptotic signals and perturbation of this balance contributes to the pathogenesis in a variety of vascular diseases, including retinal neovascularization. The long-term goal of this project is to develop a better understanding of the pathogenesis of retinal neovascularization in order to design and develop new therapeutic strategies for proliferative retinopathies. Objectives of the current proposal are to determine the pro-apoptotic pathways and mechanisms that regulate the development and subsequent regression of retinal neovascularization. The central hypothesis of this proposal is that directly modulating retinal endothelial cell apoptosis (cell death) by targeting the apoptotic machinery will be an effective anti-angiogenic approach regardless of pro-angiogenic stimulus. In order to test our hypothesis and identify mechanisms that are responsible for vascular tuft apoptosis, we will use the mouse model of oxygen-induced retinopathy and mouse model of diabetic retinopathy. We propose the following specific aims: 1) Characterize the contribution of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and its receptors to neovascular tuft regression, 2) Identify intracellular apoptotic regulators of retinal vaso-obliteration and preretinal neovascular tuft regression, specifically the BCL-2 family of pro-apoptotic proteins, and 3) Identify the contribution of p53-dependent apoptosis to neovascular tuft regression. Genetically altered mice, agonist antibodies, soluble proteins and small molecule inhibitors will be used to characterize pro-apoptotic pathways that modulate retinal endothelial cell apoptosis and pathologic neovascularization. The loss- and gain-of-function in vivo studies in the current proposal are an important means to better understand molecular pathways that control the balance between anti-apoptotic (angiogenic) and pro-apoptotic (anti-angiogenic) factors in the retina. Our characterization of the specific death signals that help regulate retinal neovascularization should help refine and offer opportunities to develop new therapeutic strategies for both ROP and diabetic retinopathy. PUBLIC HEALTH RELEVANCE: Retinopathy of prematurity (ROP) is a disorder of abnormal blood vessels in the developing eyes of premature infants and may result in blindness. Current laser treatments can alter the disease process but are destructive to the retina. This project aims to identify molecules that are capable of inducing cell death in the abnormal blood vessels, thus leading to the development of new and complementary treatment strategies for ROP.